Mimicking angiogenic microenvironment of alveolar soft- part sarcoma in a microfluidic coculture vasculature chip

• 成果类型: Article
• 署名作者: Chuaychob, Surachada; Lyu, Ruyin; Tanaka, Miwa; Haginiwa, Ayumi; Kitada, Atsuya; Nakamura, Takuro; Yokokawa, Ryuji
• 署名单位: Kyoto University; Japanese Foundation for Cancer Research; Tokyo Medical University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13721
• DOI: 10.1073/pnas.2312472121
• 发表日期: 2024-03-26
• 关键词: large-scale; tumor; platform; GROWTH; models

摘要

Alveolar soft - part sarcoma (ASPS) is a slow- growing soft tissue sarcoma with high mortality rates that affects adolescents and young adults. ASPS resists conventional chemotherapy; thus, decades of research have elucidated pathogenic mechanisms driving the disease, particularly its angiogenic capacities. Integrated blood vessels that are rich in pericytes (PCs) and metastatic potential are distinctive of ASPS. To mimic ASPS angiogenic microenvironment, a microfluidic coculture vasculature chip has been developed as a three- dimensional (3D) spheroid composed of mouse ASPS, a layer of PCs, and endothelial cells (ECs). This ASPS - onachip provided functional and morphological similarity as the in vivo mouse model to elucidate the cellular crosstalk within the tumor vasculature before metastasis. We successfully reproduce ASPS spheroid and leaky vessels representing the unique tumor vasculature to assess effective drug delivery into the core of a solid tumor. Furthermore, this ASPS angiogenesis model enabled us to investigate the role of proteins in the intracellular trafficking of bioactive signals from ASPS to PCs and ECs during angiogenesis, including Rab27a and Sytl2. The results can help to develop drugs targeting the crosstalk between ASPS and the adjacent cells in the tumoral microenvironment. Significance The in vitro model of alveolar soft - part sarcoma (ASPS) comprehensively mimicked the complex angiogenesis ASPS environment with abundant pericytes- rich and perfusable vascular networks. Compared to the conventional avascular tumor spheroid models, our ASPS - onachip, comprising a mouse ASPS spheroid and pericyteendothelial cell coculture, replicates the in vivo tumor vasculature that is rich in pericytes, enabling the study of cellular interactions before metastasis. Besides, the ASPS - onachip provided functional and morphological similarity as the in vivo mouse model, which helps to investigate the role of Rab27a and Sytl2 in intracellular signaling during tumor vessel formation. These findings are crucial for developing targeted therapies that disrupt the cellular communication within the tumor microenvironment, potentially offering broad avenues for ASPS treatment.